Bibliographic details of publications referred to in this specification are collected alphabetically at the end of the description.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.
Heart failure (HF) is a complex disease state broadly defined by an inability of the heart to pump sufficiently to cope with its venous return and/or to deliver sufficient output to meet the metabolic demands of the body. Severe heart failure is an increasingly common, life-threatening cardiovascular disorder, characterized by marked disability, frequent hospitalization and high mortality. HF is increasingly prevalent in older individuals (up to 10% of the population) and it has become the most common cause for hospitalization in people >65 yrs. HF is a leading cause or contributor to hospitalization and therefore is emerging as a substantial contributor to healthcare spending. The particular clinical manifestations of HF are determined by the underlying cause of the heart failure.
The term heart failure (HF) refers broadly to a pathophysiologic disorder in which cardiac performance is incapable of delivering sufficient blood to meet metabolic demand (e.g. during physical activity or in severe cases at rest), or to accommodate venous return. A range of further sub-classifications can then be applied, however in the commonest clinical paradigm HF is considered according to symptoms of reduced cardiac output leading to easy fatigue and organ dysfunction (e.g. renal), and to symptoms related to congestion either in the lungs (causing breathlessness) or peripherally (leading to swelling of the lower limbs and abdomen). HF is the most common chronic cardiovascular disorder. In the US approximately 5,000,000 patients have heart failure and of these up to 15-20% have the most advanced forms. It is particularly prevalent in older individuals (up to 10% of the general population >70 yrs) and it has become the most common cause for hospitalization in people >65 yrs. Recurrent hospitalization is frequent, with 25% of patients re-admitted within one month of an admission and >50% will be re-admitted within 6 months. The average US cost of an HF admission is >$20,000, with an average length of stay of four to five days.
Many patients suffering from HF have impaired left ventricular (LV) myocardial function. However, HF may be associated with a wide variety of LV dysfunctions. These range from patients with normal LV size and preserved ejection fraction to those with severe dilation of LV and/or markedly reduced ejection fraction (Yancy et al).
Ejection fraction (EF) is considered an important classification in heart failure patients because of patient demographics, comorbid conditions, prognosis and response to therapies and the patients for clinical trials are often selected on the basis of EF (Yancy et al).
HF with reduced EF (HFrEF) has an EF or 40%. Randomised controlled therapeutic trials mainly enroll patients with HFrEF and it is only these patients that have efficacious therapies to date (Yancy et al).
HF with preserved EF (HFpEF) refers to patients having an EF of >40%, with those having an EF from 40 to 49% being considered borderline HFpEF. Several criteria have been proposed to define or diagnose HFpEF including:                i. clinical signs and symptoms of HF;        ii. evidence of preserved or normal LVEF; and        iii. evidence of LV diastolic dysfunction that can be determined by Doppler echocardiography or cardiac catheterization.        
At present, in contrast to HFrEF there are no efficacious therapies for HFpEF (Yancy et al, Loffredo et al).
For patients with advanced HFrEF that require hospitalization, the use of positive inotropes such as intravenous dobutamine and milrinone, to stimulate cardiac contraction is common. Recently an oral controlled-release formulation for treating such patients has been developed (WO 2013/023250). Furthermore, the use of long-term inotropic support for “no option” patients, that is, those patients not suitable for heart transplantation or artificial heart transplant, has recently been advocated by the American Heart Association Guidelines for treatment of HFrEF.
A number of therapies for HFpEF have been proposed (Kamajda and Lam, Sharma and Kass) including β-blockers and calcium channel blockers, ACE inhibitors and angiotensin receptor blockers and digoxin, each with little or no conclusive benefit. A recent study with spironolactone (Edelmann et al), an aldosterone receptor blocker improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms or quality of life in HFpEF patients. Another recent study with the phosphosiesterase-5 inhibitor sildenafil (RELAX study) did not result in improvement in exercise capacity or clinical status in HFpEF patients (Redfield et al). A clinical trial with Ranolazine, a selective inhibitor of late sodium current, also did not result in a change in echocardiographic parameters or exercise performance in HFpEF patients (Komajda and Lam). Some new approaches have had come promising effects in preclinical or early clinical studies, including neprilysin inhibitors, soluble guanylate cyclase stimulators and advanced glycation end products, but have not been yet fully investigated.
Inotropes have not been investigated in HFpEF patients because contractile function is generally thought to be normal or only mildly reduced. Hence those treating heart failure patients would not recommend the use of drugs such as milrinone to treat HFpEF patients based on present literature.
There is a need for therapies that improve one or more of the clinical symptoms of HFpEF.